The detrimental effects of elevated perioperative blood glucose have been reported in a large and growing body of peer-reviewed medical publications. Pre-operative and intraoperative hypoglycemia and hyperglycemia have been reported as independent risk factors for postoperative complications, including infection and death. In modern surgical suites there are limited space and personnel available for monitoring patient blood analytes, though studies have shown the importance for tightly controlled glucose during cardiothoracic and other major surgical procedures. The current method for monitoring patient blood glucose is to obtain a sample of the patient's blood and have it sent to the hospital lab for analysis, or to a nearby point-of-care laboratory system. These procedures lack sufficient accuracy, take too long, and require that limited staff take time away from critical functions to draw a blood sample, analyze it, or send it off to the hospital's lab for analysis (and wait for results). The time lag between sampling and delivery of results is detrimental to optimum blood glucose management.
The “Portland Protocol” (Furnary 2004), where insulin is continuously provided to the patient during open heart surgical procedures, was developed to keep blood glucose from rising above 180 mg/dL, but does not address hypoglycemic (low blood glucose) conditions that lead to other postoperative complications. Tight glucose control, targeting concentrations between 80-120 mg/dL has been shown in published studies to reduce postoperative complications. These complications include mediastinitis or deep sternal wound infection, loss of mental acuity, respiratory infections, and death. Reduced mortality, reduced morbidity, lower incidence of surgical site infections, enhanced long term survival, and reduction in lost mental acuity are benefits of maintaining blood glucose concentrations below 180 mg/dL. Of the seventy-five percent of patients that lose some mental acuity during surgery about 50% regain normal function over the next year. Hypoglycemia during surgery has been associated with this loss, and more frequent monitoring of patients before, during, and after surgery to maintain optimal blood glucose events will provide for faster healing and improved patient outcomes.
There are currently no automated blood glucose monitoring systems utilized to monitor critically ill patients or perioperatively. Some companies have developed implantable monitors for use in critical care settings, but none for intraoperative monitoring.
Prior art products include an implantable catheter that would be expected to add complexity to the number of attachment's (IV's, monitors, oxygen, etc.) to the patient. It is used in conjunction with an injectable compound that provides fluorescence in the presence of glucose. Little is known about how this might interact with the hemoconcentrator or heart-lung bypass process, in addition to a lack of measurement precision and sensitivity.
Another prior art product provides an implantable sensor that takes readings from interstitial fluid collected via microdialysis and transmits them via RFID to a monitor within five feet of the patient. It has received CE Mark as a Class II A medical device. It has been designed for use in clinical settings by healthcare professionals, but requires calibration with inaccurate and labor intensive fingerstick or laboratory analysis.
While continuous monitors based on microdialysis technologies for diabetic patients have been released to market in the United States, they are not stand-alone monitors, and require that the patient calibrate and make adjustments to treatment (insulin injection or medication) based on readings from old inaccurate existing finger-stick method and monitor, or confirmation readings from clinical laboratory devices.
The current method for measuring glucose during surgery is to draw a blood sample and send it to the hospital's lab for analysis and wait for results to be returned to the surgical suite. Time between testing and receipt of results can be more than an hour, and presumably because of this, patient sampling is done at least on an hourly basis during cardiothoracic surgeries that last on average about six hours, which does not provide sufficiently frequent measurement to permit timely adjustment of insulin and/or glucose.
Over the past decade, the occurrence of one of the worst postoperative complications, namely deep sternal wound infection, has been increasing. Rates that used to be 1% or less are now occurring in 2-3% of cases, and in some hospital systems in more than 4%. The incidence of diabetes, and therefore the number of diabetic patients undergoing surgery has increased, pushing mortality, morbidity, and hospitals costs upwards.
A variety of clinical procedures have been implemented that have helped slow the increase in the incidence of deep sternal wound infections, but none has addressed it as sufficiently as shown in the clinical studies over the past four years. These measures include antibiotic treatments, wound care solutions (platelet rich plasma), hand washing, and reduction of surgical personnel moving in and out of the surgical suite.
Microdialysis based continuous monitors remain targeted at the much larger consumer monitor market, and have not yet been applied successfully to perioperative monitoring, and continue to be used as ancillary products to track trends as opposed to adjusting or directing treatment, due to their lack of sufficient accuracy and necessary precision.
The prior art includes an injectable product that glows in the presence of glucose, however the results obtained are general in nature and not sufficiently specific to provide guidance in therapeutic treatment. Microdialysis based monitors incorporate a minimally invasive sensor that is implanted in the skin of the patient. Most utilize RFID or Bluetooth technology to transmit measurement data to the monitors, again with high costs and insufficient measurement precision.
The prior art also includes a number of devices that measure blood glucose, none of which has been applied to the specifications or the working environment found in cardiothoracic and other major surgeries, or intensive care units. Most require too much hands-on effort, frequent calibration, implantables, transmission radio frequencies, or other issues that would preclude their providing the required accurate, safe, convenient, and automated real-time measurement system that displays results on-demand.
Conventional methods for relatively crude industrial measurement of chiral analytes (sugars such as glucose) are shown in U.S. Pat. No. 3,411,342. This polarimeter consisted of a light source, collimating lens, a primary polarizer to establish a reference point for measurement of optical rotation, a sample cell through which a continuous stream of crude syrup was circulated, and a measuring circuit that determined the extent of optical rotation caused by the sample through an appropriate output signal. Visible light sources in the 400-700 nm wavelength were typical with this type of polarimeter. The minute concentrations of glucose that are present in the human body are far below the sensitivity provided by such polarimeters.
It is well known that glucose in solution is an optically active material. Due to its molecular structure it will cause the plane of polarization of light to be passing through the solution to be changed. The quantitative relationship between the amount of polarization rotation, the glucose concentration, and the length of the optical path through which the light travels has been clearly established. This is expressed mathematically as:Aθ=α*L*C Where:                Δθ is the polarization change in degrees;        α is the specific rotation constant dependent on the specified glucose type and the wavelength of the light source;                    α: 56.5 degrees per decimeter per gram per milliliter for a-d-glucose at a wavelength of 633 nanometers;                        L is the path length of the optical path containing the glucose solution in decimeters (dm) where (1 dm: 10 cm, or 10 centimeters); and        C is the concentration of the glucose solution in grams (g) per 100 milliliters (ml) of solution or g/dL (from “Sugar Analysis” 3rd Edition, Browne & Zerban, John Wiley & Sons, 1941, page 263).        
For the clinically meaningful glucose concentration of 40 to 400 mg/dL (milligrams per deciliter) and a path length of 5 cm (centimeters) the observed rotation ranges from about 0.0112° to 0.11275° for a wavelength of 633 nanometers (nm) As the wavelength of the light source is increased the specific rotation decreases, to a value of 26.3° per decimeter per gram per milliliter for a-d-glucose at a wavelength of 900 nanometers. At that wavelength the rotation in the above case is reduced to 0.0052 and 0.052° respectively.
If the assumption is made that there is about a 10% change in the optical transmission through the 5 cm path of a flow cell; then a 5 cm path length through the flow cell should produce about 0.0042 to 0.047° of polarization rotation. Thus, a usable system must have a basic sensitivity on the order of about 0.0042° degrees, i.e., 14 arc-second, or 70 microradians, with a 5 cm flow cell.
U.S. Pat. No. 5,209,231 by Cote, et al., describes a non-invasive glucose sensor which utilizes a pair of polarizers, a quarter wave plate and a motor driven polarizer which produces a constant amplitude phase modulated beam. This beam is split into two beams, one of which passes through the sample and the other which is employed as a reference. By phase demodulation of the two beams, each incident on a different detector, a measure of glucose concentration in an optical cell is determined. Measurements are proposed to be made transversely through the eye's anterior chamber. This approach suffers in sensitivity of measurement (according to the authors) which is probably due to noise problems associated with the motor driven phase modulator as well as other unidentified problems.
“Multispectral Polarimetric Glucose Detection using a Single Pockels Cell”, Optical Engineering, Vol. 33, pp 2746 (1994) by King, et al., describes a system which employs a pair of polarizers, a quarter wave plate, and a Pockels cell modulator which are configured as a polarization spectrometer. They employed the output from a lock-in amplifier which is “filtered using a leaky integrator” and then fed back to a compensator circuit which was eventually summed with the driver oscillator output and then input to the Pockels cell driver to null the AC signal in the system. Again, noise levels in the system represent the major problem in achieving the required sensitivity. The reported data show a scatter that is unacceptable for a working blood glucose sensor.
Similarly, Pockels cell modulation has been employed for differential analysis of chiral analytes in flow cells (U.S. Pat. No. 5,168,326). By applying oscillating voltage to the Pockels cell, alternating beams of circular and linearly polarized light are produced. Greater sensitivity is achieved through effectively removing noise by subtracting the rotation angles calculated for each of the beams.
The analysis techniques for chiral analytes such as glucose have been improved in the area of noise reduction. There are various single beam methods utilizing electronic or optical means to filter noise (as an example, WO 01/06918). Additional methods utilize dual beams either by comparison to a reference cell (U.S. Pat. No. 4,912,059), mixing out of phase sinusoidal signals (U.S. Pat. No. 5,477,327), switching between a signal and reference beam (U.S. Pat. No. 5,621,528), or using a two frequency laser source with two orthogonal linear polarized waves (U.S. Pat. Nos. 5,896,198 and 6,327,037). Glucose measurement is based on ascertaining the change in optical rotation (transmission) from the optical null point.
The inventor has developed patented prior art utilizing modulated sources (U.S. Pat. No. 6,999,808, U.S. Pat. No. RE39642, U.S. Pat. No. RE40316, and U.S. Pat. No. 6,370,407) demonstrating methods and devices for precisely extracting signals out of the noise, and provided greater sensitivity and stability than required. The methods therein described suffer from a common problem of cost and complexity that reduce their commercial utility from a practical standpoint.
Thus, there remains a need to provide a more practical, cost effective, and accurate automated method for quantifying the change in optical rotation introduced by a chiral analyte, such as glucose, by reducing the noise associated with the measurement and moving away from predictive mathematics in favor of direct measurement.